The basic objectives of this application are the development and application of the tandem [4+2]/[3+2] cycloaddition reactions of two 2-azoniaheterodienes, the nitroalkene and N-vinylnitrone groups. The program is divided into two major sections with different specific aims but unified in the common theme of new reaction chemistry for the preparation of natural and non-natural heterocyclic compounds. The methodological objective relating to nitroalkenes is subdivided into two parts. The first will involve the expansion of the established cycloaddition chemistry of nitroalkenes to access different size rings through: (1) dienophile variation (1- and 2-alkoxydienes), (2) the use of chiral Lewis acid catalysis the [4+2] process and (3) and investigation of modified dipolarophiles to incorporate larger rings after [3+2] cycloaddition. The second part of the methodological study is the exploration and development of the intra/intra [4+2]/[3+2] tandem cycloadditions. This new family of transformations will allow for the rapid and selective construction of complex polycyclic ring systems from simple acyclic precursors. A major activity will be the assessment of scope, viability and stereocontrol elements in selected permutations of this class. Synthetic targets for the tandem nitroalkene cycloaddition include natural compounds in a number of alkaloid families. Scandine (a melodinus alkaloid) UCS1025A/B (a rare pyrrolizidine alkaloid) and daphnilactone (a daphniphyllum alkaloid) are chosen to highlight the strategic power of different tandem processes. The intriguing new class of 1-azafenestranes will also be prepared to assess the distortion of the central carbon. The second major section of the proposal is the invention, development and exploration of the cycloaddition chemistry of N-vinylnitrones, a new family of 2-azoniaheterodienes. These hybrid heterodiene/dipoles offer great potential for the general synthesis of piperidines and piperidine-embedded polycyclic compounds. The basic features of preparation, structure, stability, reactivity (in both [4+2] and [3+2] manifolds) will be addressed with particular attention to opportunities in tandem cycloadditions with intramolecularly tethered components.